Heart failure (HF) is a worldwide epidemic that contributes considerably to the overall cost of health care in developed nations. The number of people afflicted with this complex disease is increasing at an alarming pace-a trend that is likely to continue for many years to come. The overall goals of our proposed research are to identify the mechanical culprits that dictate the bifurcation of the system from the stable healthy state into the instable state of HF and to determine the borderline between physiological/compensatory and pathophysiological/non-compensatory growth and remodeling (G&R). To address these goals, our research approach is to experimentally inform and validate multiscale laws of myocardial growth and remodeling (G&R) using three different clinically relevant large animal HF preparations in order to predict the propensity of patients with a myocardial infarction (MI) developing HF. Our specific Aim 1 is to elucidate a predictive validated multiscale law of myocardial G&R in eccentric hypertrophy associated with cardiac dilation. We hypothesize that a fiber-strain-based growth law can predict cardiac G&R in response to volume-overload, i.e., elevated myofiber strains stimulate concentric growth. Competing hypotheses based on stress-, strain rate-, and strain energy will be tested. Aim 2 is to validate a predictive multi-scale law of myocardial G&R in concentric hypertrophy associated with wall thickening. We hypothesize that a unified cross-fiber strain based growth law can predict cardiac G&R in response to pressure-overload. Similar competing hypotheses as in Aim 1 will be tested. In Aim 3, we will apply these G&R laws to predict the propensity for HF in ischemic heart disease based on specific mechanical indices of myocardial function. We hypothesize that there exists a threshold of a maximal rate of change of strain in reference to sarcomere length, above which compensatory G&R is not possible and the physiological negative feedback loop to maintain homeostasis gives way to a positive feedback loop that leads to progress remodeling and ultimate demise of the myocardium. Successful completion of this work will provide a fundamental understanding of the response of myocardium to mechanical stimuli that has substantial clinical relevance. Scientifically, this approach will provide the first ever validated and calibrated predictive micro-structural model of myocardial growth and remodeling that is fundamental to cardiology, tissue engineering, cardiac rehabilitation, and cardiac surgery. Clinically, we will provide a specific mechanical index to predict the propensity of HF in ischemic heart disease that may have a significant healthcare implication.